Mechanisms of pancreatic carcinogenesis with respect to its cellular origin

• Applicant: Professor Dr. Guido von Figura
• Subject Area: Gastroenterology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274390078

Pancreatic ductal adenocarcinoma (PDAC) is associated with an extremely poor prognosis. Therefore, a better understanding of initiation and progression of PDAC is of paramount interest in order to develop novel diagnostic and therapeutic tools. The aim of this proposal is to characterize the mechanisms of pancreatic carcinogenesis from its precursor lesions, pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). This study is based on previous work of the applicant, where it was shown that the chromatin remodeler Brg1 has an important but opposed role during initiation of acinar-derived PanINs and duct-derived IPMNs. A deletion of Brg1 in a genetically engineered mouse model led to a blockage of oncogenic Kras driven PanIN formation from acinar cells. In contrast, Brg1 loss sensitized ductal cells for oncogenic Kras induced formation of IPMN lesions.In this proposal it is aimed to investigate the basis for the opposed function of Brg1 during the development of PDAC precursor lesions from their originating cells. To this end, the effect of Brg1 loss on acinar cell plasticity and regeneration as wells as acinar to ductal reprogramming and PanIN initiation will be analyzed. Besides the identification of Brg1-regulated targets that influence acinar cell transformation, the epigenetic control of these genes by Brg1 will be examined. Moreover, by using a genetically engineered mouse model that allows independent recombination of the Kras and Brg1 alleles, the function of Brg1 in the progression of PDAC will be analyzed. Finally, the role of Brg1 during human pancreatic carcinogenesis will be studied by immunohistochemical analyses. A further goal of this proposal is the examination of IPMN formation from pancreatic duct cells. To this end, LKB1 and p16 will be deleted in KrasG12D expressing duct cells. LKB1 and p16 are Brg1-regulated genes and also frequently mutated in human pancreatic cancer, which suggests a role for these genes in the IPMN-mouse model as well as in human IPMN formation.The here proposed studies may lead to the identification of novel molecular targets that will be of interest for early identification as well as therapy of PDAC.

• DFG Programme: Independent Junior Research Groups